MYC overexpression in natural killer cell lymphoma: prognostic and therapeutic implications
Chengfeng Bi,
Yuhua Huang,
Roshia Ali,
Fang Wang,
Xia Yang,
Alyssa Bouska,
Lu Xu,
Xinbao Hao,
Matthew A. Lunning,
Wing C. Chan,
Javeed Iqbal,
Dennis D. Weisenburger,
Julie M. Vose,
Kai Fu
Affiliations
Chengfeng Bi
Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE
Yuhua Huang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong
Roshia Ali
Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE
Fang Wang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China; Department of Molecular Diagnosis, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong
Xia Yang
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China; Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong
Alyssa Bouska
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
Lu Xu
Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA; Department of Hematology, The First Affiliated Hospital of Hainan Medical University, Haikou, Hainan
Xinbao Hao
State Key Laboratory of Membrane Biology, School of Medicine, Tsinghua University, Beijing
Matthew A. Lunning
Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE
Wing C. Chan
Department of Pathology, City of Hope National Medical Center, Duarte, CA
Javeed Iqbal
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
Dennis D. Weisenburger
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
Julie M. Vose
Division of Oncology and Hematology, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE
Kai Fu
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA; Department of Pathology, Roswell Park Comprehensive Cancer Center, Buffalo, NY
The current clinical management of Extranodal NK/T-cell lymphoma (ENKTL) primarily depends on conventional chemotherapy and radiotherapy, underscoring the need for innovative therapeutic strategies. This study explores the clinical significance and therapeutic implication of c-MYC (MYC) in ENKTL. Initially, we identified MYC protein overexpression in approximately 75% of cases within a large cohort of 111 patients. MYC overexpression was strongly correlated with lymphoma cell proliferation and poor clinical outcomes. Intriguingly, integrating MYC expression into the PINK-E prognostic model significantly enhanced its predictive power. Subsequently, we implemented MYC knockdown (KD) in NK malignancy cell lines with MYC overexpression, resulting in significant viability reduction. RNA-sequencing (RNA-seq) used to determine MYC function revealed a high overlap with canonical MYC-regulated genes and enrichment in metabolism and cell cycle regulation. Integrative analysis of the RNA-seq data upon MYC KD with gene expression profiles of primary ENKTL cases identified a subset of genes closely associated with MYC overexpression. Among these, CDK4 emerged as a potential therapeutic target, and its inhibition not only abrogated MYC function but also decreased MYC expression in NK malignancy cells. Furthermore, the clinical-grade CDK4/6 inhibitor palbociclib exhibited a potent anti-tumor effect in xenograft mouse models, especially when combined with gemcitabine. In summary, our study firmly establishes MYC as an oncogene with prognostic significance in ENKTL and highlights CDK4 inhibition as a promising therapeutic strategy for treating ENKTL with MYC overexpression.
